Successful siRNA therapy requires suitable delivery systems with targeting moieties such as small molecules, peptides, antibodies, or aptamers. Galactose (Gal) residues recognized by the asialoglycoprotein receptor (ASGPR) can serve as potent targeting moieties for hepatocellular carcinoma (HCC) cells. However, efficient targeting to HCC via galactose moieties rather than normal liver tissues in HCC patients remains a challenge. To achieve more efficient siRNA delivery in HCC, we synthesized various galactoside derivatives and investigated the siRNA delivery capability of nanoparticles modified with those galactoside derivatives. In this study, we assembled lipid/calcium/phosphate nanoparticles (LCP NPs) conjugated with eight types of galactoside derivatives and demonstrated that phenyl β-d-galactoside-decorated LCP NPs (L4-LCP NPs) exhibited a superior siRNA delivery into HCC cells compared to normal hepatocytes. VEGF siRNAs delivered by L4-LCP NPs downregulated VEGF expression in HCC in vitro and in vivo and led to a potent antiangiogenic effect in the tumor microenvironment of a murine orthotopic HCC model. The efficient delivery of VEGF siRNA by L4-LCP NPs that resulted in significant tumor regression indicates that phenyl galactoside could be a promising HCC-targeting ligand for therapeutic siRNA delivery to treat liver cancer.

中文翻译：

---

半乳糖衍生物修饰的纳米粒子高效siRNA传递到肝细胞癌。

成功的siRNA治疗需要具有靶向部分（例如小分子，肽，抗体或适体）的合适递送系统。脱唾液酸糖蛋白受体（ASGPR）识别的半乳糖（Gal）残基可作为肝细胞癌（HCC）细胞的有效靶向部分。然而，在肝癌患者中，通过半乳糖部分而不是正常肝组织有效靶向肝癌仍然是一个挑战。为了在HCC中实现更有效的siRNA递送，我们合成了各种半乳糖苷衍生物，并研究了用这些半乳糖苷衍生物修饰的纳米颗粒的siRNA递送能力。在这项研究中，我们组装了与八种半乳糖苷衍生物共轭的脂质/钙/磷酸盐纳米颗粒（LCP NPs），并证明了苯基β- d与正常肝细胞相比，用半乳糖苷修饰的LCP NP（L4-LCP NP）表现出更好的siRNA递送至HCC细胞。L4-LCP NPs递送的VEGF siRNA在体外和体内下调了HCC中VEGF的表达，并在鼠原​​位HCC模型的肿瘤微环境中产生了有效的抗血管生成作用。通过L4-LCP NP有效递送VEGF siRNA，导致肿瘤显着消退，表明苯基半乳糖苷可能是有希望的靶向HCC的配体，可用于治疗性siRNA的递送以治疗肝癌。